Pd(II)Cl2 mediated oxidative cyclisation of hydroxy-vinylfurans to lactols: Synthesis of Hagen's gland lactones

Article abstract of DOI:10.1016/S0040-4020(00)00099-5

A concise synthesis of Hagen's gland lactones 3-6 by a chiron approach starting from D-mannose is described. Transformation of o-mannose to dihydroxy-vinylfuran 8 followed by Pd(II)Cl₂ mediated oxidative cyclisation to obtain the tetrahydrofurofuran diol 7 constituted the key reaction in the total synthesis of 3-6. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00099-5

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 3021±3026
Pd(II)Cl2 Mediated Oxidative Cyclisation of
Hydroxy-Vinylfurans to Lactols:
Synthesis of Hagen's Gland Lactones
*
Hari Babu Mereyala, Rajendrakumar Reddy Gadikota, K. Sugnana Sunder and S. Shailaja
Organic Chemistry Division III, Indian Institute of Chemical Technology, Hyderabad 500-007, India
Received 23 November 1999; revised 5 January 2000; accepted 27 January 2000
AbstractÐA concise synthesis of Hagen's gland lactones 3±6 by a chiron approach starting from d-mannose is described. Transformation
of d-mannose to dihydroxy-vinylfuran 8 followed by Pd(II)Cl2 mediated oxidative cyclisation to obtain the tetrahydrofurofuran diol 7
constituted the key reaction in the total synthesis of 3±6. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
®rst enantiospeci®c synthesis of 5(R)-Hagen's gland
lactones 3 and 4 from d-glucose by Wittig-ole®nation-
cyclisation protocol.5
Hagen's glands located near the abdominal tips of the
Braconid
wasps,
Diachasmimorpha
longicaudata
Now we report synthesis of bicyclic lactones 3±6 by Pd(II)
catalysed oxidative cyclisation of hydroxy-vinylfurans6 by
the method that was earlier developed by us for the
construction of tetrahydrofurofurans and demonstrated for
the synthesis of goniofufurone analogues7,8 and (1)-trans
kumausyne.9
(Ashmead), Diachasmimorpha tryoni (Cameron) and fopius
(Biosteres) arisanus contain fragrant volatile biological
control agents that are rich in lactones. There has been
considerable interest in the study of their biological
role.1,2 Williams and coworkers have tentatively charac-
terised these lactones as octan-4-olide 1, dodecan-4-olide
2, bicyclic lactones (3aa, 5b, 6aa)-5-n-butyl tetrahydro-
furo-[3,2-b]furan-2(3H)-one 3 and the 5-n-hexyl derivative
4 respectively based on NMR considerations.3 Kitching et
al.4 have established the absolute stereochemistry of 1±4 by
ef®cient synthesis and enantioselective gas chromato-
graphy. 1 and 2 were synthesized starting from (S)-glutamic
acid and assigned (R)-con®guration at C-5; bicyclic lactones
5(R) cis-3 and 5(R) cis-4 were synthesized by palladium(II)
catalysed oxycarbonylation±lactonization reaction with an
unsaturated 1,3-diol to obtain by ¯ash chromatography
separable diastereomers of 3 and 4. The relative stereo-
chemistry of cis and trans 3 and 4 was determined by
NOE measurements and MM3 calculations.
Results and Discussion
Herein we report a concise synthesis of Hagen's gland
lactones 3±6 by the chiron approach starting from
d-mannose. From retrosynthetic analysis (Scheme 1)
lactones 3±6 could be formed from lactol 7 by sequential
reactions such as homologation and oxidation. Lactol 7
could be derived from dihydroxy-vinylfuran 8 by means
of the Pd(II)Cl2 mediated oxidative cyclisation protocol
developed earlier in our laboratory.6±8 Hydroxy-vinylfuran
8 in turn could be obtained from diacetone-d-mannose10 (9)
by well established reactions.
9 Was reacted with carboethoxymethylene triphenyl-
phosphorane in acetonitrile at re¯ux temperature for 6 h to
obtain a diastereomeric mixture of C-glycosides 10 (a/b 1:1
by 1H NMR)11,12 which on subsequent reduction with
lithium aluminium hydride in dry ether gave alcohol 11
(Scheme 2). Alcohol 11 was protected as benzyl ether 12.
Regioselective hydrolysis of the 5,6-O-isopropylidene
group of 12 was effected smoothly in 60% aqueous acetic
acid over 7 h at room temperature to obtain the diol 13 in
85% yield. 13 Was reacted with I2, Ph3P, imidazole
(4 mol equiv. each) in THF at re¯ux temperature for 6 h to
As part of our long term program in the fabrication of bicyclic
lactones as bioactive agents we have recently described the
Keywords: furans; lactones; Pd and related compounds; cyclisation.
* Corresponding author. Tel.: 191-40-7170275; fax: 191-40-7173387/
3757; e-mail: haribabu@iict.ap.nic.in
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00099-5

3022
H. B. Mereyala et al. / Tetrahedron 56 (2000) 3021±3026
Scheme 1.
Scheme 2. Reagents and conditions: (a) Ph3PvCHCOOEt, ACN, re¯ux, 6 h, 84%; (b) LAH, Ether, re¯ux, 3 h, 82%; (c) NaH, BnBr, DMF, 08C!RT, 1 h,
94%; (d) 60% aq. HOAc, RT, 7 h, 85%; (e) I2, TPP, Imidazole, THF, re¯ux, 6 h, 86%; (f) 5% aq. H2SO4, Dioxane, re¯ux, 3 h, 81%; (g) PdCl2, CuCl, DMF:H2O
(4:1), O2, RT, 24 h, 84%; (h) Methanolic HCl, RT, 4 h, 88%; (i) CS2±NaH±MeI, THF, 08C!RT, 1 h, 92%; (j) nBu3SnH, AIBN, Toluene, re¯ux, 6 h, 69%; (k)
Li, liq. NH3, 2208C, 30 min, 73%; (l) Oxalyl chloride, DMSO, TEA, CH2Cl2, 2788C, 1 h; (m) Ph3PvCH±CH3 and Ph3PvCHCH2CH2CH3, THF, 08C!RT,
2 h, 76%; (n) Raney Ni, H2, EtOH, 4 h, 98%; (o) Aq. HCl, THF, 508C, 1 h, 76%; (p) PDC, CH2Cl2, re¯ux, 1 h, 33±38%.

H. B. Mereyala et al. / Tetrahedron 56 (2000) 3021±3026
3023
obtain vinylfuran 14 in 86% yield.13,14 14 Was characterised
from the H NMR spectrum by the appearance of vinylic
spectrometer with CDCl3 as internal standard (dc 77.0) for
solutions in deuteriochloroform. Optical rotations were
measured with a JASCO DIP-370 instrument and [a]D
values are in units of 1021 deg cm2 g21. IR spectra were
taken with a Perkin±Elmer 1310 spectrometer. Organic
solutions were dried over anhydrous Na2SO4 and concen-
trated below 408C in vacuo. All moisture sensitive reactions
were performed under a nitrogen atmosphere using ¯ame
dried glassware. Solvents were dried over standard drying
agents and freshly distilled prior to use.
1
protons at d 5.2±5.45 (2H, m) and 5.85±6.1 (1H, m). The
2,3-O-isopropylidene protecting group of 14 was removed
by re¯uxing for 3 h in dioxane containing 5% of H2SO4 to
obtain hydroxy-vinylfuran 8. 8 was subjected to intra-
molecular Pd(II)Cl2 mediated oxidative cyclisation8±10
with a catalytic amount of PdCl2, CuCl, water:DMF (1:4)
while oxygen was continuously bubbled for 24 h at
room temperature to give a diastereomeric mixture of lactol
1
7 (1:1 by H NMR) as a thick syrup in 84% yield. 7 was
characterised from the 1H NMR spectrum by the appearance
of H-2 protons at d 1.79±2.3 (m) and H-1 at d 5.44±5.78
(m).
3,6-Anhydro-2-deoxy-4,5:7,8-di-O-isopropylidene-d-
glycero-d-talo/galacto octitol (11). A solution of ester 1011
(30.0 g, 90.6 mmol) in dry diethyl ether (400 ml) was added
to an ice cooled and stirred suspension of lithium aluminium
hydride (5.16 g, 135.6 mmol) in dry diethyl ether (300 ml)
under nitrogen atmosphere. The reaction mixture was
re¯uxed for 3 h and quenched with successive addition of
EtOAc (30 ml), water (30 ml) and 20% NaOH solution
(30 ml). The reaction mixture was ®ltered through celite
and the ®lter cake was washed with diethyl ether
(2£300 ml). The combined ethereal layers were dried
(Na2SO4), concentrated to a syrupy residue and ®ltered on
a bed of silica gel (60±120 mesh, hexane:EtOAc, 2:1) to
obtain the title compound 11 (21.6 g, 82%) as a thick
Lactol 7 was treated with methanolic hydrochloric acid to
obtain the corresponding methylfuranoside 15 as a syrup in
88% yield. 15 was reacted with NaH±CS2±MeI to obtain
xanthate 16 which on further reaction with n-Bu3SnH at
re¯ux temperature in toluene containing a catalytic amount
of AIBN gave the deoxy derivative 17 in 69% yield. 17 Was
characterised from the appearance of H-3, H-6 protons
between d 1.15±2.4. Debenzylation of 17 was effected in
Li, liq. NH3 at 2208C for 30 min to obtain alcohol 18 as a
syrup in 73% yield. Swern oxidation (COCl2/DMSO/Et3N)
of alcohol 18 gave an aldehyde which was immediately
reacted with alkylidene triphenylphosphoranes (C2H5P1
Ph3Br2 and n-C4H9P1Ph3Br2, NaNH2, THF) to obtain
ole®ns 19 and 20 respectively, which were characterised
1
syrup. [a]Dˆ27.04 (c 1.0, CHCl3). H NMR (200 MHz,
CDCl3): d 1.36, 1.42, 1.45, 1.50, 1.52 (12H, 5s, 4£CH3),
1.6±2.15 (2H, m, H-2), 3.5±4.82 (9H, m, H-1,3-8). Anal.
Calcd for C14H24O6: C, 58.30; H, 8.39. Found: C, 58.48; H,
8.45.
1
from the H NMR spectrum by the appearance of ole®nic
protons at d 5.38±5.75 (m, 2H). 19 and 20 were hydro-
genated [Raney Ni, EtOH, H2 (1 atm)] to yield 21 and 22,
respectively, in quantitative yield. 21 and 22 were treated
with aq. HCl in THF at 508C for 1 h to obtain the corre-
sponding lactols which were oxidised with PDC to obtain
the desired Hagen's gland lactones 3±6 which were sepa-
rated by column chromatography. 3 Was characterised from
the 1H NMR spectrum by the appearance of H-3a at d 4.80
(ddd, 1H, Jˆ6.4, 4.5, 0.7 Hz) and H-6a at d 5.11 (dd, 1H,
Jˆ4.9, 4.5 Hz). Compound 5 was characterised from the 1H
NMR spectrum by the appearance of H-3a at d 4.45 (ddd,
1H, Jˆ4.0, 6.0, 1.0 Hz) and H-6a at d 4.9 (dd, 1H, Jˆ6.0,
3,6-Anhydro-1-O-benzyl-2-deoxy-4,5:7,8-di-O-isopropyl-
idene-d-glycero-d-talo/galacto octitol (12). To a slurry of
hexane washed sodium hydride (2.1 g, 87.0 mmol) in dry
N,N-dimethylformamide (40 ml) was added a solution of 11
(21.0 g, 72.6 mmol) in DMF (45 ml) at 08C. To this suspen-
sion was added dropwise benzyl bromide (13.8 g,
81.0 mmol) and the mixture was stirred for 1 h at room
temperature. When reaction was complete, excess of
sodium hydride was quenched by addition of methanol
(10 ml), the reaction mixture was poured into ice-cold
water (500 ml) and extracted into diethyl ether
(2£300 ml). The combined ethereal extracts were dried
(Na2SO4), ®ltered and concentrated to obtain a residue
which was ®ltered on a bed of silica gel (60±120 mesh,
hexane:EtOAc, 4:1) to obtain the title compound 12
1
3.8 Hz). 3,4 and 5,6 were virtually identical in H NMR
spectra; they differ only in the integration of aliphatic
1
protons between d 0.8±1.8. H and 13C NMR data of 3
and 4 were in agreement with that reported in the
literature.3,5
(25.8 g, 94%) as a syrup. [a]Dˆ22.4 (c 1.0, CHCl3). H
1
NMR (200 MHz, CDCl3): d 1.3, 1.42, 1.48, 1.50, 1.53
(12H, 5s, 4£CH3), 1.72 (1H, dd, Jgemˆ14.1, 4.6 Hz, H-2),
2.0 (1H, dd, H-20), 3.39±4.75 (11H, m, H-1,3±8 and
OCH2Ph), 7.18±7.41 (5H, m, ArH). Anal. Calcd for
C21H30O6: C, 66.63; H, 7.99. Found: C, 66.87; H, 8.15.
In conclusion, enantiospeci®c syntheses of 3±6 have been
achieved by the chiron approach starting from d-mannose
involving Pd(II)Cl2 mediated oxidative cyclisation of
hydroxy-vinylfuran 8 to lactol 7 as a key step. Determi-
nation of the biological roles of 3±6 is in progress due to
their availability in multigram amounts and will be reported
elsewhere.
3,6-Anhydro-1-O-benzyl-2-deoxy-4,5-O-isopropylidene-
d-glycero-d-talo/galacto octitol (13).
A mixture of
compound 12 (25.2 g, 66.6 mmol) and 60% aq. acetic acid
(250 ml) was stirred at room temperature for 7 h. Reaction
was monitored by TLC and when complete, acetic acid was
removed by azeotropic distillation with toluene in vacuo to
obtain a syrupy residue, which was ®ltered on a bed of silica
gel (60±120 mesh, hexane:EtOAc, 3:1) to obtain the title
compound 13 (19.2 g, 85%) as a thick syrup. [a]Dˆ23.4
Experimental
1H NMR spectra were measured with a Varian Gemini (200
and 400 MHz) spectrometer, with tetramethylsilane as
internal standard for solutions in deuteriochloroform. 13C
NMR spectra were taken with a Varian Gemini (50 MHz)
1
(c 1.0, CHCl3). H NMR (200 MHz, CDCl3): d 1.32, 1.48,

3024
H. B. Mereyala et al. / Tetrahedron 56 (2000) 3021±3026
1.51 (6H, 3s, 2£CH3), 1.68±2.2 (2H, m, H-2,20), 3.5±2.75
(2H, br s, OH), 3.41±4.89 (11H, m, H-1,3±8 and OCH2Ph),
7.21±7.42 (5H, m, ArH). Anal. Calcd for C18H26O6: C,
63.87; H, 7.75. Found: C, 64.12; H, 7.83.
3.48±4.85 (8H, m, H-2,3,3a,6a, CH2CH2OBn and
OCH2Ph), 5.44±5.78 (1H, m, H-1), 7.18±7.41 (5H, m,
ArH). Anal. Calcd for C15H20O5: C, 64.26; H, 7.20.
Found: C, 64.39; H, 7.27.
3,6-Anhydro-1-O-benzyl-2,7,8-trideoxy-4,5-O-isopropyl-
idene-d-talo/galacto-oct-7-enitol (14). To a solution of diol
13 (18 g, 52.8 mmol) in toluene (500 ml) containing tri-
phenylphosphine (55.8 g, 213.0 mmol) and imidazole
(14.46 g, 213.0 mmol) at 508C was added iodine (53.4 g,
213.0 mmol) and re¯uxed for 6 h. Progress of the reaction
was monitored by TLC, when the reaction was complete
solvent was removed under vacuum, to obtain a thick
syrup. It was dissolved in EtOAc (500 ml), 5% aqueous
NaOH solution (150 ml) was added, organic layer was sepa-
rated and aqueous layer was extracted into EtOAc (300 ml).
The pooled organic phase was washed with water (150 ml),
saturated sodium thiosulphate (150 ml) and water (150 ml).
The organic phase was separated, concentrated to a residue
and ®ltered on a bed of silica gel (60±120 mesh, hexane:
EtOAc, 6:1) to obtain the title compound 14 (13.92 g, 86%)
(2R/S, 3R,3aS,5R/S,6aR)-2-Benzyloxy ethyl-5-methoxy-
[3,2-b]furan-3-ol (15). A solution of lactol 7 (7.8 g,
27.6 mmol) in 2% methanolic hydrochloric acid (120 ml)
was stirred for 4 h at room temperature. Progress of the
reaction was monitored by TLC, when the reaction was
complete, Ba2CO3 (5 g) was added and ®ltered. Filtrate
was concentrated to a syrupy residue, which was ®ltered
on a bed of silica gel (60±120 mesh, hexane:EtOAc, 4:1)
to obtain the title compound 15 (7.2 g, 88%) as a thick
syrup. [a]Dˆ36.1 (c 0.7, CHCl3). 1H NMR (200 MHz,
CDCl3): d 1.8±2.38 (4H, m, H-6,60 and CH2CH2OBn),
2.55 (br s, OH), 3.31±3.41 (3H, 2s, OMe), 3.46±5.3 (9H,
m, H-2,3,3a,5,6a, CH2CH2OBn and OCH2Ph), 7.18±7.41
(5H, m, ArH). Anal. Calcd for C16H22O5: C, 65.27; H,
7.54. Found: C, 65.32; H, 7.58.
1
as a colourless oil. [a]Dˆ227.3 (c 1.5, CHCl3). H NMR
(2R/S, 3R,3aS,5R/S,6aR)-2-Benzyloxy ethyl-5-methoxy-
3-O-(S-methyldithio-carbonate)-[3,2-b]furan (16). To a
solution of 15 (6.6 g, 22.5 mmol) in THF (150 ml) was
added hexane washed sodium hydride (0.78 g, 33.6 mmol)
and carbon disul®de (3.48 g, 44.4 mmol) at 08C. After stir-
ring for 15 min iodomethane (4.8 g, 33.9 mmol) was added
and brought to room temperature. After completion of the
reaction (30 min), excess sodium hydride was quenched by
addition of glacial acetic acid. Solution was ®ltered, concen-
trated to a syrupy residue, which was extracted into diethyl
ether (450 ml). The ethereal layer was washed with water,
dried (Na2SO4), ®ltered and concentrated to obtain the title
compound 16 (7.92 g, 92%) as an oil. [a]Dˆ51.4 (c 1.0,
(200 MHz, CDCl3): d 1.29, 1.48, 1.49 (6H, 3s, 2£CH3), 1.76
(1H, dd, Jgemˆ14.0, 4.2 Hz, H-2), 2.05 (1H, dd, H-20),
3.52±4.38 (4H, m, H-1,10, 3 and H-6), 4.5 (2H, s,
OCH2Ph), 4.51±4.70 (2H, m, H-4 and H-5), 5.2±5.45
(2H, m, H-8, 80), 5.85±6.10 (1H, m, H-7), 7.15±7.45 (5H,
m, ArH). Anal. Calcd for C18H24O4: C, 71.01; H, 7.95.
Found: C, 71.17; H, 8.18.
3,6-Anhydro-1-O-benzyl-2,7,8-trideoxy-d-talo/galacto
oct-7-enitol (8). To a solution of 14 (13.2 g, 43.38 mmol) in
dioxane (60 ml) was added 5% aq. H2SO4 (10 ml) and the
reaction mixture was re¯uxed for 3 h. After completion of
the reaction, solvent was removed under vacuum and
extracted into EtOAc (450 ml). Organic phase was washed
with saturated NaHCO3 solution (150 ml), water (150 ml),
dried (Na2SO4) and concentrated to obtain a residue, which
was ®ltered on a bed of silica gel (60±120 mesh, hexane:
EtOAc, 3:1) to obtain the title compound 8 (9.24 g, 81%) as
1
CHCl3). H NMR (200 MHz, CDCl3): d 1.82±2.32 (4H,
m, H-6,60 and CH2CH2OBn), 2.59, 2.61 (3H, 2s, SMe),
3.32, 3.36, 3.4 (3H, 3s, OCH3), 3.48±5.22 (8H, m,
H-2,3a,5,6a, CH2CH2OBn and OCH2Ph), 5.8±6.0 (1H, m,
H-3), 7.18±7.44 (5H, m, ArH). Anal. Calcd for C18H24O5S2:
C, 56.23; H, 6.30. Found: C, 56.39; H, 6.42.
1
a syrup. [a]Dˆ1.4 (c 0.9, CHCl3). H NMR (200 MHz,
CDCl3): d 1.89±2.3 (2H, m, H-2,20), 3.48±4.6 (6H, m,
H-1,3±6), 4.51 (2H, s, OCH2Ph), 5.2±5.4 (2H, m, H-8,80),
5.80±6.10 (1H, m, H-7), 7.2±7.40 (5H, m, ArH). Anal.
Calcd for C15H20O4: C, 68.15; H, 7.63. Found: C, 68.28;
H, 7.74.
(2R/S,3aS,5R/S,6aR)-2-Benzyloxy ethyl-5-methoxy-[3,2-
b]furan (17). A solution of xanthate 16 (7.8 g, 20.1
mmol) tri-n-butyltin hydride (9.0 g, 30.6 mmol) and AIBN
(40 mg) in toluene (450 ml) was re¯uxed for 6 h. When
reaction was complete, solvent was removed under reduced
pressure to obtain a residue, which was ®ltered on a bed of
silica gel (60±120 mesh, hexane:EtOAc, 7:1) to obtain the
title compound 17 (3.9 g, 69%) as a colourless oil. [a]Dˆ
68.3 (c 1.1, CHCl3). 1H NMR (200 MHz, CDCl3): d 1.15±
2.4 (6H, m, H-3,30,6,60 and CH2CH2OBn), 3.28,3.3,3.38
(3H, 3s, OCH3), 3.5±3.7 (2H, m, CH2CH2OBn), 3.89±
4.15 (1H, m, H-6a), 4.4±5.18 (5H, m, H-2,3a,5 and
OCH2Ph), 7.15±7.4 (5H, m, ArH). Anal. Calcd for
C16H22O4: C, 69.03; H, 7.97. Found: C, 69.09; H, 8.03.
(2R/S, 3R,3aS,5R/S,6aR)-2-Benzyloxy ethyl[3,2-b]furan-
3,5-diol (7). To a solution of diol 8 (9.0 g, 34.0 mmol) in
20% aq. DMF (60 ml) was added Pd(II)Cl2 (0.12 g,
0.68 mmol), CuCl (3.37 g, 34.0 mmol) and oxygen was
bubbled for 24 h at room temperature. Progress of the reac-
tion was monitored by TLC, when the reaction was
complete the reaction mixture was diluted with diethyl
ether (450 ml), ®ltered through a bed of silica gel and eluted
with diethyl ether (300 ml). The combined ethereal layers
were washed with 2% aq. HCl (200 ml) and water
(2£100 ml). Organic phase was separated, dried (Na2SO4),
concentrated to obtain a residue, which was ®ltered on a bed
of silica gel (60±120 mesh, hexane:EtOAc, 2:1) to obtain
the title compound 7 (8.04 g, 84%) as a thick syrup.
[a]Dˆ12.1 (c 1.0, CHCl3). 1H NMR (200 MHz,
CDCl3): d 1.79±2.3 (4H, m, H-6,60 and CH2CH2OBn),
(2R/S,3aR,5R/S,6aR)-2-Hydroxy ethyl-5-methoxy-[3,2-
b]furan (18). To a solution of 17 (3.5 g, 12.6 mmol) in
liq. ammonia (60 ml) at 2208C was added lithium (0.15 g,
25.0 mmol) and stirred for 30 min. After completion of the
reaction, it was brought to room temperature and quenched
with solid NH4Cl. This residue was extracted into ethyl ace-
tate (200 ml) and washed with water, dried (Na2SO4)

H. B. Mereyala et al. / Tetrahedron 56 (2000) 3021±3026
3025
concentrated to a syrupy residue which was ®ltered on a bed
of silica gel (60±120 mesh, hexane:EtOAc, 3:1) to obtain
the title compound 18 (1.71 g, 73%) as a colourless oil.
2-Hexyl-(5R/S)-methoxy(2R/S,3aR,6aR)-perhydrofuro[3,2-
b]furan (22). Prepared from ole®n 20 (0.6 g, 2.64 mmol) as
described for the compound 21 to obtain the title compound
22 (0.6 g, 98%) as a colourless oil. [a]Dˆ42.6 (c 1.0,
m, H-3,30,6,60 and n-C6H13), 3.31,3.34 (3H, 2s, OCH3),
3.58±5.25 (4H, m, H-2,3a,5,6a). Anal. Calcd for
C13H24O3: C, 68.37; H, 10.60. Found: C, 68.42; H, 10.66.
1
[a]Dˆ86.5 (c 1.0, CHCl3). H NMR (200 MHz, CDCl3): d
1
1.2±2.42 (6H, m, H-3,30,6,60 and CH2CH2OH), 3.35,3.37,
3.4 (3H, 3s, OMe), 3.65±3.9 (2H, m, CH2CH2OH), 4.05±
5.2 (4H, m, H-2,3a,5 and 6a). Anal. Calcd for C9H16O4: C,
57.41; H, 8.57. Found: C, 57.47; H, 8.62.
CHCl3). H NMR (200 MHz, CDCl3): d 0.79±2.41 (17H,
2-[(E)-2-Butenyl]-5R/S-methoxy(2R/S,3aR,6aR)-perhydro-
furo[3,2-b]furan (19). Dry dichloromethane (15 ml)
containing dimethylsulfoxide (0.63 g, 6.6 mmol) was
added to a solution of oxalyl chloride (0.84 g, 6.6 mmol)
in dry dichloromethane (10 ml) at 2788C and stirred for
20 min under nitrogen atmosphere. A solution of alcohol
18 (0.78 g, 4.2 mmol) in dry dichloromethane (6 ml) was
added to the above reaction mixture and stirred for 45 min
followed by the addition of triethylamine (1.32 g,
13.2 mmol). The reaction mixture was brought gradually
to room temperature and diluted with dichloromethane
(90 ml). The organic phase was washed with brine
(75 ml), dried (Na2SO4) and evaporated to obtain the alde-
hyde as a syrup which was immediately reacted with a
solution of ethylidene triphenylphosphorane (generated in
situ from n-C2H5P1Ph3Br2 (3.0 g, 7.8 mmol), NaNH2
(0.27 g, 7.2 mmol), THF (75 ml)) under nitrogen atmos-
phere for 1.5 h at 2208C. The reaction mixture was then
quenched with saturated aq. NH4Cl (75 ml) and was
extracted into diethyl ether (2£75 ml). Combined ethereal
layers were washed with water (75 ml), dried (Na2SO4) and
concentrated to a syrupy residue which was ®ltered on a bed
of silica gel (60±120 mesh, hexane:EtOAc, 6:1) to obtain
the title compound 19 (0.63 g, 77%) as a colourless oil. [a]D
(3aR,5R,6aR)-5-Butylperhydrofuro[3,2-b]furan-2-one
(3) and (3aR,5S,6aR)-5-butylperhydrofuro[3,2-b]furan-
3-one (5). A solution of compound 21 (0.57 g, 2.85 mmol)
in THF (15 ml) and 20% aqueous HCl (3 ml) was stirred for
1 h at 458C. After completion of the reaction, reaction
mixture was neutralised with sodium hydrogen carbonate
and ®ltered. The ®ltrate was concentrated and extracted
with ethyl acetate (75 ml), organic phase was washed with
water, dried (Na2SO4), concentrated to obtain the lactol
(0.39 g, 76%). Lactol was dissolved in dry dichloro-
methane (30 ml) and oxidised with pyridinium dichromate
(0.87 g, 2.52 mmol) at re¯ux temperature for 45 min. When
the reaction was complete, celite (3 g) and diethyl ether
(75 ml) were added to the reaction mixture and ®ltered.
The ®ltrate concentrated to a syrupy residue which was
chromatographed (60±120 mesh, hexane:EtOAc, 4:1) to
elute ®rst 3 (0.174 g, 33%). [a]Dˆ149.9 (c 1.0, CHCl3);
1
IR (neat): n 2930, 2825, 1770, 1190, 1050 cm21; H NMR
(200 MHz, CDCl3): d 0.8±1.9 (10H, m, H-6 and n-C4H9),
2.38 (dd, 1H, Jˆ14.2, 4.2 Hz, H-6), 2.64 (dd, 1H, Jˆ19.0,
0.7 Hz, H-3), 2.75 (dd, 1H, Jˆ19.0, 6.4 Hz, H-3), 4.07
(dddd, 1H, Jˆ10.0, 7.2, 5.1, 4.2 Hz, H-5), 4.80 (ddd, 1H,
Jˆ6.4, 4.5 0.7 Hz, H-3a) 5.11 (dd, 1H, Jˆ4.9, 4.5 Hz,
H-6a). Anal. Calcd for C10H16O3: C, 65.19; H, 8.75.
Found: C, 65.25; H, 8.80.
1
82.5 (c 0.7, CHCl3). H NMR (200 MHz, CDCl3): d 1.52±
2.6 (9H, m, H-H-3,30,6,60 and n-C4H7), 3.38,3.4 (3H, 2s,
OCH3), 3.9±4.14 (1H, m, H-2), 4.51±5.29 (3H, m,
H-3a,5,6a), 5.38±5.75 (2H, m, n-C4H7 ole®nic). Anal.
Calcd for C11H18O3: C, 66.62; H, 9.16. Found: C, 66.68;
H, 9.22.
Followed by 5 (0.183 g, 35%) as a colourless oil.
[a]Dˆ124.9 (c 1.3, CHCl31); IR (neat): n 2931, 2820,
1771, 1193 and 1048 cm21; H NMR (200 MHz, CDCl3):
d 0.8±2.5 (11H, m, H-6,60 and n-C4H9), 2.65 (dd, 2H,
Jˆ16.0, 4.0 Hz, H-3,30), 3.8±3.98 (m, 1H, H-5), 4.45
(ddd, 1H, Jˆ4.0, 6.0, 1.0 Hz, H-3a), 4.95 (dd, 1H, Jˆ6.0,
3.8 Hz, H-6a). Anal. Calcd for C10H16O3: C, 65.19; H, 8.75.
Found: C, 65.28; H, 8.82.
2-[(E)-2-Hexenyl]-5R/S-methoxy(2R/S,3aR,6aR)-perhydro-
furo[3,2-b]furan (20). Prepared from alcohol 18 (0.72 g,
3.81 mmol), n-C4H9P1Ph3Br2 (3.0 g, 7.56 mmol) and
NaNH2 (0.27 g, 6.9 mmol) as described for compound 19
to obtain the title compound 20 (0.66 g, 76%) as a colourless
oil. [a]Dˆ76.1 (c 0.5, CHCl3). 1H NMR (200 MHz, CDCl3):
d 1.5±2.65 (9H, m, H-3,30,6,60 and n-C6H11), 3.39,3.41 (3H,
2s, OCH3), 3.8±4.16 (1H, m, H-2), 4.48±5.3 (3H, m,
H-3a,5,6a), 5.35±5.75 (2H, m, n-C6H11 ole®nic). Anal.
Calcd for C11H18O3: C, 68.98; H, 9.80. Found: C, 69.04;
H, 9.87.
(3aR,5R,6aR)-5-Hexylperhydrofuro[3,2-b]furan-2-one
(4) and (3aR,5S,6aR)-5-hexylperhydrofuro[3,2-b]furan-
3-one (6). Prepared from compound 22 (0.54 g, 2.4 mmol)
to obtain the title compounds 4 (0.174 g, 36%) and 6
(0.18 g, 38%) as colourless syrups.
Spectral data of 4 [a]Dˆ150.01 (c 1.0, CHCl3); IR (neat): n
1
2928, 2850, 1770, 1190, 1045 cm21; H NMR (200 MHz,
2-Butyl-(5R/S)-methoxy(2R/S,3aR,6aR)-perhydrofuro[3,2-
b]furan (21). A solution of 19 (0.6 g, 3.0 mmol) was
subjected to hydrogenation with Raney-Nickel catalyst
(approximately 0.2 g) for 2 h under hydrogen atmosphere
(1 atm). The catalyst was ®ltered off and the ®ltrate was
concentrated to obtain the title compound 21 (0.594 g,
CDCl3): d 0.8±1.9 (14H, m, H-6 and n-C6H13), 2.38 (dd,
1H, Jˆ14.2, 4.2 Hz, H-6), 2.64 (dd, 1H, Jˆ19.0, 0.7 Hz,
H-3), 2.75 (dd, 1H, Jˆ19.0, 6.4 Hz, H-3), 4.07 (dddd, 1H,
Jˆ10.0, 7.2, 5.1, 4.2 Hz, H-5), 4.80 (ddd, 1H, Jˆ6.4, 4.5,
0.7 Hz, H-3a), 5.11 (dd, 1H, Jˆ4.9, 4.5 Hz, H-6a). Anal.
calcd for C12H20O3: C, 67.89; H, 9.50. Found: C, 67.99;
H, 9.56.
1
99%) as a syrup. [a]Dˆ38.6 (c 1.03, CHCl3). H NMR
(200 MHz, CDCl3): d 0.8±2.4 (13H, m, H-3,30,6,60 and
n-C4H9), 3.3,3.33 (3H, 2s, OCH3), 3.6±5.2 (4H, m,
H-2,3a,5,6a). Anal. Calcd for C11H20O3: C, 65.95; H,
10.07. Found: C, 66.11; H, 10.12.
Spectral data of 6 [a]Dˆ124.6 (c 1.3, CHCl3); IR (neat): n
1
2925, 2850, 1770, 1190, 1045 cm21; H NMR (200 MHz,
CDCl3): d 0.8±2.5 (15H, m, H-6,60 and n-C6H13), 2.65 (dd,

3026
H. B. Mereyala et al. / Tetrahedron 56 (2000) 3021±3026
2H, Jˆ16.0, 4.0 Hz, H-3,30), 3.8±3.98 (m, 1H, H-5), 4.45
(ddd, 1H, Jˆ4.0, 6.0, 1.0 Hz, H-3a), 4.95 (dd, 1H, Jˆ6.0,
3.8 Hz, H-6a). Anal. Calcd for C12H20O3: C, 67.89; H, 9.50.
Found: C, 67.95; H, 9.58.
7. Mereyala, H. B.; Gadikota, R. R.; Krishnan, R. J. Chem. Soc.
Perkin Trans. 1 1997, 3567±3571.
8. Mereyala, H. B.; Gadikota, R. R.; Joe, M.; Arora, S. K.;
Dastidar, S. G.; Agarwal, S. Bioorg. Med. Chem. 1999, 9, 2095±
2103.
9. Fernandez de la Pradilla, R.; Montero, C.; Priego, J.;
Martinezcruz, L. A. J. Org. Chem. 1998, 63, 9612±9613.
10. Schmidt, O. T. Methods Carbohydr. Chem. 1963, 2, 319±321.
11. Ohrui, H.; Jones, G. H.; Moffatt, J. G.; Maddox, M. L.;
Christensen, A. T.; Byram, S. K. J. Am. Chem. Soc. 1975, 97,
4602±4613.
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